Unremitting Asthma as a Presentation of Pulmonary Nocardiosis: A Case Report

Severe, refractory asthma requires a combination of multiple maintenance inhalers and medications including high-dose inhaled corticosteroids and immunomodulators to achieve control of symptoms. The use of inhaled corticosteroids, however, increases the susceptibility of opportunistic bacterial infections, such as Nocardia, resulting in pulmonary nocardiosis. This case describes a 46-year-old patient with a history of severe, refractory asthma who presented with progressively worsening asthma exacerbation symptoms. She was treated with immunomodulators, high-dose inhaled corticosteroids and oral steroids, and several courses of antibiotics. CT imaging revealed bibasilar peri-bronchial thickening and tree-in-bud nodularity in the right lower lobe. Pulmonary cultures collected from bronchoscopy grew Nocardia nova complex. This was a rare case of persistent asthma exacerbation by N. nova complex bronchopulmonary infection. Broad differentials should be considered in patients with severe, refractory asthma who were previously controlled and were found to fail treatment therapies. Immunocompromised patients with chronic lung disease are at higher risk of severe infection with disseminated nocardiosis. These patients have a higher mortality and morbidity risk if early diagnosis of pulmonary nocardiosis does not occur.


Introduction
Nocardia is an opportunistic actinomycete found in ubiquitous environments and easily transmissible through inhalation or direct skin inoculation.The bacteria primarily affect up to 30% of immunocompetent patients who will more frequently have cutaneous involvement and approximately 60% of immunocompromised hosts who are more likely to suffer from pulmonary involvement [1,2].More severe pulmonary disease states transpire in immunocompromised patients such as those on high-dose oral or inhaled steroids, transplant patients, patients receiving chemotherapy, and those with autoimmune diseases, chronic lung disease, and any condition with a cell-mediated immunity deficiency [3].Patients with chronic structural lung diseases include those with bronchiectasis, interstitial lung disease, asthma, and most commonly chronic obstructive pulmonary disease [4].
Pulmonary nocardiosis is more frequently observed as the lungs are the most affected site second to skin involvement.There is an increased risk of mortality with dissemination to other organ systems, especially the central nervous system.This prompts for early identification and treatment [5,6].Early diagnosis is difficult as the clinical presentation and radiographic findings can be nonspecific, often mimicking other disease processes and malignancies [7].Prolonged duration of respiratory symptoms of a productive cough and dyspnea may be one of the only systemic findings prior to further workup.
Patients with severe, refractory asthma require an extensive regimen of high-dose inhaled corticosteroids (ICS) with or without oral steroids, controller medications, and immunomodulators to obtain relative symptom control.In cases where patients are adherent to their appropriate regimen and have worsening symptoms, an underlying infection should be considered as the etiology for new onset prolonged and treatment-resistant exacerbations.This case presents a rare case of severe, refractory asthma exacerbation from pulmonary nocardiosis with one of the most common pathogenic Nocardia species, Nocardia nova complex.

Case Presentation
A 46-year-old female with a history of severe, refractory asthma and recent coronavirus disease 2019 (COVID-19) infection presented with a five-month history of persistent chest congestion, wheezing, a productive cough, pleuritic chest pain, worsening exercise intolerance, and intermittent subjective fevers.The patient reported worsening asthmatic symptoms despite being on maximum maintenance therapy for asthma including Zafirlukast, fluticasone-umeclidinium-vilanterol inhaler, benralizumab, fluticasone inhaler, and as needed albuterol inhaler.The patient completed two rounds of oral antibiotics with doxycycline and cefdinir, as well as several courses of oral prednisone without improvement in symptoms.
Vitals were all within normal limits.On evaluation, diffuse wheezing was heard throughout all lung fields.No rales or rhonchi were appreciated.The remainder of the physical exam was within normal limits.Pulmonary function tests (PFT) were indicative of large and small airway obstructions with small airway reversibility worse than previous PFTs.Chest x-rays showed left lower lobe airspace disease consistent with pneumonia.CT imaging of the chest (Figure 1) demonstrated mild to moderate linear nodular opacities in the right lower lobe.Sputum cultures collected initially did not grow organisms.The patient was later referred to pulmonology and underwent bronchoscopy with bronchial alveolar lavage (BAL).The bronchoscopy revealed a large amount of thick and gelatinous secretions in her airways.The respiratory cultures from the BAL grew N. nova complex.The patient was referred to Infectious Disease and started on trimethoprim/sulfamethoxazole (TMP-SMX) for the treatment of pulmonary nocardiosis.Serial CT imaging of the chest revealed persistent bibasilar peribronchial thickening and tree-in-bud nodularity that was slightly increased in the right lower lobe with new left upper lobe ground glass opacities.There were no cavitary lesions, consolidations, or pleural effusions noted.MRI of the brain was also ordered to rule out disseminated nocardiosis and central nervous system involvement.Benralizumab was held until the patient completed the six-month course of TMP-SMX.While receiving TMP-SMX, the patient's asthma symptoms and PFTs improved; however, the TMP-SMX course was prolonged to a 12-month course due to persistent complaints of a productive cough and abnormal CT chest findings.

Discussion
Severe, refractory asthma is characterized as persistent asthma symptoms despite maximizing maintenance therapy with high-dose ICS-long-acting β-agonist (LABAs), and appropriate management of co-morbidities.High-dose steroids are crucial in this patient population in that the airway smooth muscle cells are less responsive to corticosteroids compared to patients with mild or moderate asthma.Patients will also experience worsening symptoms with a decreased dosage of ICS [8].These patients often require dual therapy with prolonged oral corticosteroids in addition to the high dose ICS, multiple controller agents including LABA, short-acting β-agonist (SABA), theophylline, or leukotriene antagonists.Many patients remain symptomatic and require adjuvant therapy with immunomodulators such as IgE, IL-4 receptor, and IL-5Ra inhibitors [9].The treatment regimen raises a concern for immunosuppression with the use of corticosteroids and immunomodulators in combination with airway epithelial dysfunction predisposing to acute pulmonary infections.
Several theories exist proposing the mechanism of pneumonia and opportunistic bacterial infections.The chronic inflammation associated with asthma induces goblet cell hyperplasia and increased mucin production resulting in impaired clearance of both colonized and pathogenic bacteria in the lower respiratory tract [10].Furthermore, ICS alters the host mucosal defense system allowing for bacterial infiltration; however, these studies were supported in chronic obstructive pulmonary disease (COPD) patients [11].Although there has not been a significant association between pulmonary infections with immunomodulator use, studies have shown a dose-dependent relationship with ICS, specifically with fluticasone, resulting in an increased susceptibility to pneumonia [8,[12][13][14].
Multiple studies compared the use of fluticasone versus budesonide in the increased risk of communityacquired pneumonia.There has been controversial data indicating a protective effect with the use of budesonide in preventing pneumonia or a lack of association between the two [8,11,14,15].Considering that high-dose ICS is essential for the treatment of severe, refractory asthma, pneumonia can be suspected in patients treated with high-dose fluticasone as our patient was.In addition, patients with recent viral infections are at risk of damage to the respiratory barrier with concurrent immune system dysfunction further creating conditions of opportunistic bacterial or fungal infections [16].
Immunocompromised patients or those with underlying structural lung disease and concurrent oral or inhaled corticosteroids use at risk of developing invasive nocardiosis [17].Pulmonary nocardiosis is one of the most common sites of infection since inhalation is a primary route of entry for Nocardia.Asthma patients with impaired airway clearance and immune dysfunction from steroid use have an increased chance of Nocardia colonization with progression to pulmonary nocardiosis [17,18].The prognosis of pulmonary nocardiosis is dependent on prompt diagnosis; however, initial presentation can be non-specific or with delayed symptom presentation.Radiographic studies can mimic other pulmonary diseases with findings of consolidations, pulmonary nodules, cavitary lesions, interstitial patterns, pleural effusions, and even chest wall extensions [1,3,6].Diagnosis may require invasive procedures including bronchoscopy with BAL, lung biopsy, or needle aspiration as sputum samples are often inconclusive [18].Once a diagnosis is established, the duration of treatment is expected for 6-12 months with either monotherapy with sulfonamides, TMP-SMX, or combination therapy by adding cotrimoxazole, linezolid, amikacin, cephalosporins, or carbapenems [19].Pulmonary involvement may require combination therapy according to the severity of the disease and concerns of antibiotic resistance to prevent relapses [7].In several studies, patients were treated with TMP-SMX primarily, and carbapenems were added on in severe pulmonary disease and with dissemination [2,5].
With the rarity of Nocardia infections, there is a lack of formal guideline-directed treatment compared to other infections [2].Although there are multiple studies and case reports published, there is a lack of clinical trials to determine optimal therapies and inconsistency with the in vitro and in vivo antibiotic susceptibilities [20].Multiple studies reported treatment with sulfonamides, although antibiotic and antimicrobial susceptibility testing is recommended to identify specific Nocardia strains and determine susceptibility patterns.Various Nocardia species have different resistance patterns, particularly with commonly used TMP-SMX [20].Consequently, antibiotic treatment is prolonged or relapse with disease progression has been described in certain cases [20].Further studies are needed to determine primary treatments for immunocompromised patients with nocardiosis.
It is to be noted that the patient in the current report was diagnosed with COVID-19 several months prior to diagnosis with pulmonary nocardiosis.There have multiple documented cases of nocardiosis during or after COVID-19 infection in patients with risk factors predisposing them to a Nocardia infection after steroid use.However, these patients experienced a rapid onset of symptoms or were diagnosed with Nocardia within 5-50 days with concurrent ICS use during their hospitalization [20].The patients were likely colonized with Nocardia species prior to viral infection and the use of steroids [16].The combination of viral infection with additional immunosuppression from chronic steroid use provided an ideal environment for a superimposed Nocardia infection [16].However, our patient was already treated with long-term oral and inhaled steroids at the time of her COVID-19 diagnosis.She completed a course of casirivimab-imdevimab and oral prednisone taper in (no listing of months, days, years) with a resolution of her sinus symptoms.Her worsening asthma symptoms appeared two to three months period after her COVID-19 infection.The patient's imaging at the time of the COVID-19 infection and follow-up imaging did not show signs of lower lobe infiltration observed with the Nocardia infection until months later.Although the COVID-19 infection was a likely risk factor predisposing to the Nocardia infection, we believe that the patient's pulmonary nocardiosis was related to persistent high-dose ICS use.

Conclusions
Immunocompromised patients are at risk for invasive nocardiosis and dissemination to other organ systems

FIGURE 1 :
FIGURE 1: Regression of pulmonary nocardiosis during the treatment course from May 2022 to December 2022.(A, C) CT chest from May 2022 revealed mild linear opacities mostly in the right lower lobe; (B, D) Follow-up CT chest in December 2022 after seven months of treatment with TMP-SMX revealed bibasilar peribronchial thickening and tree-in-bud nodularity slightly increased in the right lower lobe and decreased in the left lower lobe.TMP/SMX: trimethoprim/sulfamethoxazole